Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple-negative breast cancer in TBCRC 030.

BACKGROUND: We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy. PATIENTS AND METHODS: We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence. RESULTS: Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10-4 (range 7.9 × 10-7-4.9 × 10-1). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12. CONCLUSIONS: Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.

TBCRC 030: a phase II study of preoperative cisplatin versus paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker.

BACKGROUND: Cisplatin and paclitaxel are active in triple-negative breast cancer (TNBC). Despite different mechanisms of action, effective predictive biomarkers to preferentially inform drug selection have not been identified. The homologous recombination deficiency (HRD) assay (Myriad Genetics, Inc.) detects impaired double-strand DNA break repair and may identify patients with BRCA1/2-proficient tumors that are sensitive to DNA-targeting therapy. The primary objective of TBCRC 030 was to detect an association of HRD with pathologic response [residual cancer burden (RCB)-0/1] to single-agent cisplatin or paclitaxel. PATIENTS AND METHODS: This prospective phase II study enrolled patients with germline BRCA1/2 wild-type/unknown stage I-III TNBC in a 12-week randomized study of preoperative cisplatin or paclitaxel. The HRD assay was carried out on baseline tissue; positive HRD was defined as a score ≥33. Crossover to an alternative chemotherapy was offered if there was inadequate response. RESULTS: One hundred and thirty-nine patients were evaluable for response, including 88 (63.3%) who had surgery at 12 weeks and 51 (36.7%) who crossed over to an alternative provider-selected preoperative chemotherapy regimen due to inadequate clinical response. HRD results were available for 104 tumors (74.8%) and 74 (71.1%) were HRD positive. The RCB-0/1 rate was 26.4% with cisplatin and 22.3% with paclitaxel. No significant association was observed between HRD score and RCB response to either cisplatin [odds ratio (OR) for RCB-0/1 if HRD positive 2.22 (95% CI: 0.39-23.68)] or paclitaxel [OR for RCB-0/1 if HRD positive 0.90 (95% CI: 0.19-4.95)]. There was no evidence of an interaction between HRD and pathologic response to chemotherapy. CONCLUSIONS: In this prospective preoperative trial in TNBC, HRD was not predictive of pathologic response. Tumors were similarly responsive to preoperative paclitaxel or cisplatin chemotherapy.

A single U/C nucleotide substitution changing alanine to valine in the beet necrotic yellow vein virus P25 protein promotes increased virus accumulation in roots of mechanically inoculated, partially resistant sugar beet seedlings.

Beet necrotic yellow vein virus (BNYVV) A type isolates E12 and S8, originating from areas where resistance-breaking had or had not been observed, respectively, served as starting material for studying the influence of sequence variations in BNYVV RNA 3 on virus accumulation in partially resistant sugar beet varieties. Sub-isolates containing only RNAs 1 and 2 were obtained by serial local lesion passages; biologically active cDNA clones were prepared for RNAs 3 which differed in their coding sequences for P25 aa 67, 68 and 129. Sugar beet seedlings were mechanically inoculated with RNA 1+2/RNA 3 pseudorecombinants. The origin of RNAs 1+2 had little influence on virus accumulation in rootlets. E12 RNA 3 coding for V(67)C(68)Y(129) P25, however, enabled a much higher virus accumulation than S8 RNA 3 coding for A(67)H(68)H(129) P25. Mutants revealed that this was due only to the V(67) 'GUU' codon as opposed to the A(67) 'GCU' codon.

Evidence supporting nutritional interventions for persons in early stage Alzheimer's disease (AD).

The purpose of this paper is to grade research evidence supporting nutritional interventions for persons with early stage dementias and to report the recommendations of a consensus panel. Thirty four studies were reviewed in the areas of dietary restriction, antioxidants, and Mediterranean diet with strong support from epidemiological studies found in all three areas. The body of evidence to support nutritional interventions in the prevention and treatment of AD is growing and has potential as a treatment modality following translational studies.

BARCSoySNP23: a panel of 23 selected SNPs for soybean cultivar identification.

This report describes a set of 23 informative SNPs (BARCSoySNP23) distributed on 19 of the 20 soybean linkage groups that can be used for soybean cultivar identification. Selection of the SNPs to include in this set was made based upon the information provided by each SNP for distinguishing a diverse set of soybean genotypes as well as the linkage map position of each SNP. The genotypes included the ancestors of North American cultivars, modern North American cultivars and a group of Korean cultivars. The procedure used to identify this subset of highly informative SNP markers resulted in a significant increase in the power of identification versus any other randomly selected set of equal number. This conclusion was supported by a simulation which indicated that the 23-SNP panel can uniquely distinguish 2,200 soybean cultivars, whereas sets of randomly selected 23-SNP panels allowed the unique identification of only about 50 cultivars. The 23-SNP panel can efficiently distinguish each of the genotypes within four maturity group sets of additional cultivars/lines that have identical classical pigmentation and morphological traits. Comparatively, the 13 trinucleotide SSR set published earlier (BARCSoySSR13) has more power on a per locus basis because of the multi-allelic nature of SSRs. However, the assay of bi-allelic SNP loci can be multi-plexed using non-gel based techniques allowing for rapid determination of the SNP alleles present in soybean genotypes, thereby compensating for their relatively low information content. Both BARCSoySNP23 and BARCSoySSR13 were highly congruent relative to identifying genotypes and for estimating population genetic differences.

A new integrated genetic linkage map of the soybean.

A total of 391 simple sequence repeat (SSR) markers designed from genomic DNA libraries, 24 derived from existing GenBank genes or ESTs, and five derived from bacterial artificial chromosome (BAC) end sequences were developed. In contrast to SSRs derived from EST sequences, those derived from genomic libraries were a superior source of polymorphic markers, given that the mean number of tandem repeats in the former was significantly less than that of the latter ( P<0.01). The 420 newly developed SSRs were mapped in one or more of five soybean mapping populations: "Minsoy" x "Noir 1", "Minsoy" x "Archer", "Archer" x "Noir 1", "Clark" x "Harosoy", and A81-356022 x PI468916. The JoinMap software package was used to combine the five maps into an integrated genetic map spanning 2,523.6 cM of Kosambi map distance across 20 linkage groups that contained 1,849 markers, including 1,015 SSRs, 709 RFLPs, 73 RAPDs, 24 classical traits, six AFLPs, ten isozymes, and 12 others. The number of new SSR markers added to each linkage group ranged from 12 to 29. In the integrated map, the ratio of SSR marker number to linkage group map distance did not differ among 18 of the 20 linkage groups; however, the SSRs were not uniformly spaced over a linkage group, clusters of SSRs with very limited recombination were frequently present. These clusters of SSRs may be indicative of gene-rich regions of soybean, as has been suggested by a number of recent studies, indicating the significant association of genes and SSRs. Development of SSR markers from map-referenced BAC clones was a very effective means of targeting markers to marker-scarce positions in the genome.

Efficient down-regulation of the major vegetative storage protein genes in transgenic soybean does not compromise plant productivity.

Soybean (Glycine max L. Merr.) contains two related and abundant proteins, VSP alpha and VSP beta, that have been called vegetative storage proteins (VSP) based on their pattern of accumulation, degradation, tissue localization, and other characteristics. To determine whether these proteins play a critical role in sequestering N and other nutrients during early plant development, a VspA antisense gene construct was used to create transgenic plants in which VSP expression was suppressed in leaves, flowers, and seed pods. Total VSP was reduced at least 50-fold due to a 100-fold reduction in VSP alpha and a 10-fold reduction in VSP beta. Transgenic lines were grown in replicated yield trials in the field in Nebraska during the summer of 1999 and seed harvested from the lines was analyzed for yield, protein, oil, and amino acid composition. No significant difference (alpha = 0.05) was found between down-regulated lines and controls for any of the traits tested. Young leaves of antisense plants grown in the greenhouse contained around 3% less soluble leaf protein than controls at the time of flowering. However, total leaf N did not vary. Withdrawing N from plants during seed fill did not alter final seed protein content of antisense lines compared with controls. These results indicate that the VSPs play little if any direct role in overall plant productivity under typical growth conditions. The lack of VSPs in antisense plants might be partially compensated for by increases in other proteins and/or non-protein N. The results also suggest that the VSPs could be genetically engineered or replaced without deleterious effects.

Integration of pressure ulcer treatment protocol into practice: clinical outcomes and care environment attributes.

The purpose of this study was to determine if a research-based protocol for pressure ulcer treatment that had been successfully implemented in a long-term care facility was sustained over time. A secondary aim was to describe the attributes of the care environment that may have contributed to or impeded the maintenance of this protocol. A retrospective chart review was conducted of all patients who developed incident stage II, III, or IV pressure ulcers in the facility over a one-year period five years after initial implementation of a pressure ulcer treatment protocol. Data regarding ulcer characteristics and type, frequency, and duration of treatments were collected. Subjects were followed until the ulcer healed, the subject died or was discharged, or the 1-year study period ended. Care environment attributes, including patient care hours, turnover and stability rates, salaries, decision-making structures, and facility mission were obtained from the facility's Human Resource Department and existing databases in the Nursing Services Department. Outcomes of protocol implementation were defined as ulcer healing and costs associated with treatment. Costs were calculated from the provider perspective and included cost of supplies and labor consumed in providing direct pressure ulcer care. Of the 46 incident ulcers treated during the one-year study period, 40 (87%) healed and five (11%) were unhealed when the subject died. One ulcer remained unhealed at the end of the study. The total cost for treatment of these incident ulcers was $18,688, with nursing labor comprising 80% of the total expenditures. Adherence to the protocol, which contained predominantly inexpensive moist wound healing treatment options, resulted in complete healing of most pressure ulcers at a relatively low cost to the facility. The organizational environment of the facility, which maintains staffing levels and salaries at higher than national averages and promotes staff nurse accountability and decision making, may have provided the necessary climate to overcome barriers to clinical integration and sustain the desired care practices.

How accurate are chronic wound assessments using interactive video technology?

This project examined the accuracy of chronic wound assessments made using an interactive, video telecommunications system (Teledoc 5000, NEC America, Inc., Irving, TX) by comparing a nurse expert's in-person wound assessments with wound assessments made from taped Teledoc sessions. Wound assessments determined the absence or presence of nine wound characteristics instrumental in guiding treatment (e.g., tunneling, undermining, granulation tissue, necrotic tissue, epithelial tissue, purulent exudate, erythema, edema, induration). A sample of 13 paired wound observations was analyzed. The accuracy of the Teledoc technology was examined by calculating the amount of agreement between the in-person assessments and the taped Teledoc assessments for each of the nine characteristics. Agreement for eight of the nine wound characteristic exceeded 75%, suggesting this telehealth medium does not alter wound assessment data, which are essential in guiding treatment decisions. In addition to connecting the remotely based nurse with nursing expertise to improve patient care, telehealth technology seemed to increase the remotely-based nurses' knowledge of wound assessment and treatment as well.

A nursing application of telecommunications. Measurement of satisfaction for patients and providers.

Consumer and provider satisfaction is key to the continued use and expansion of telehealth technology. This pilot study compared satisfaction of providers and patients with wound consultations done in person with those done via real-time interactive video technology. Eleven telehealth consultations with a nurse expert were immediately followed by an in-person consultation with a second nurse expert. Satisfaction questionnaires were administered to patients, referring nurses, and the consultant nurse expert following both the in-person consultation and the telehealth consultation. The referring nurses (100%) were satisfied with both the telehealth and in-person consultations, noting the ability to provide better care for their patients. The patients (55%) were "very satisfied" with the telehealth consultations versus 40% satisfied with the in-person consultations. Difficulty in hearing for the patients was equal in both groups, which resulted in changes in the consultation process. The patients' difficulty in seeing the telehealth consultant was addressed through larger screens and strategic positioning to provide easier viewing for the patient and providers. The telehealth nurse consultant was satisfied overall but had some difficulty communicating. This pilot study helped provide useful information for both the telehealth and in-person consultations.

Evaluating the cost of one telehealth application connecting an acute and long-term care setting.

This article describes a study of the costs of a pilot telemedicine chronic wound consultation clinic. Cost minimization analysis is the technique used to examine the costs of the clinic. The components of cost analysis include the fixed costs of personnel and equipment and the indirect costs of circuit and line charges. Cost avoidance is also examined. Cost avoidance evaluates what costs were avoided by the use of the telemedicine clinic. Additionally, the cost perspectives of the consulting agency, the referring agency, and the patient are examined. The average cost of a chronic wound consultation was $136.16 (acute care perspective). Costs of a traditional face-to-face consultation, if the residents were transported to the acute care facility would be $246.28. Fifteen telehealth consultations per month were used to determine per consultation costs for line charges and depreciation/maintenance costs. In this pilot study, a cost savings was realized and patients benefited. Increased volume will help to offset the cost of the equipment depreciation and maintenance and make telehealth chronic wound consultations more cost effective.

Who's the boss? Family/staff partnership in care of persons with dementia.

This article provides an overview of family involvement in care intervention and its implementation with African American and Caucasian family members of persons with dementia in nursing home settings.

Early experience with 'new federalism' in health insurance regulation.

The authors monitored the implementation of the Health Insurance Portability and Accountability Act (HIPAA) from 1997 to 1999. Regulators in all states and relevant federal agencies were interviewed and applicable laws and regulations studied. The authors found that HIPAA changed legal protections for consumers' health coverage in several ways. They examine how the process of regulating such coverage was affected at the state and federal levels and under an emerging partnership of the two. Despite some early implementation challenges, HIPAA's successes have been significant, although limited by the law's incremental nature.

Outcome indicators for direct and indirect caregiving.

Informal caregiving and outcomes for caregiving are an important part of health care and of particular importance in nursing. The purpose of this research is to report the results of a survey mailed to nursing experts for validation of the outcome labels Caregiver Role Performance: Direct Care and Caregiver Role Performance: Indirect Care and their accompanying indicators. Experts were asked to rate how important the identified indicators were for assessing those two outcomes. In addition, the respondents were asked to what extent nursing interventions influence the achievement of each identified indicator for Caregiver Role Performance: Direct Care and Caregiver Role Performance: Indirect Care. In general, the validity of the concept analysis work by the caregiver focus group was supported. Ten indicators for Caregiver Performance: Direct Care were retained, 1 was dropped that was considered most appropriate for indirect care, and 3 new indicators were added to reflect the nurse experts surveyed. For Caregiver Performance: Indirect Care, all of the indicators were retained.

[Structure and quality of German-language gastroscopy information forms from the patients' viewpoint]. / Struktur- und Ergebnisqualität deutsch-sprachiger Gastroskopie-Aufklärungsbogen aus Patientensicht.

UNLABELLED: Information about procedure and risks is prerequisite for obtaining informed consent for endoscopy. This prospective and randomized investigation evaluated (i) the extent of patients' information needs and (ii) the formal quality (language, ease of understanding, length, figures etc.) of three information forms concerning upper CI-endoscopy issued in 1995 by DIOmed (1), perimed compliance (2), and PERIMED-spitta (3) as judged by the patients. (iii) Outcome quality was investigated as the influence of these forms on understanding why and how endoscopy was performed as well as the influence on feeling threatened. Furthermore patients' anxiety was assessed by using Spielberger's state-trait anxiety inventory (STAI). 218 patients completed the investigation (n = 73; 70; 75, respectively). 60% claimed the need for a detailed explanation of the planned endoscopy and 48% said they wanted exhaustive informations about potential complications and risks. The three forms (length 819, 771, 1,245 words) were entirely read by 87%, 89% and 82% of the patients. Positive language, adequate length (69%, 69%, 71%) and adequate layout were evenly attributed to the three forms. A high impact of the figures for understanding was found more frequently (48%, 46%, 35%) with (1) and (2) and language war regarded easy by 57%, 54% and 44%, respectively. Flesh's reading ease score, however, proved a sophisticated niveau of language with all three forms. The indication for endoscopy (37%, 49%, 56%) and explanation of performance (43%, 43%, 63%) was superior with (3). This form also reduced anxiety as judged by STAI-means, overall STAI-changes, and relevant changes (> or = 5 points). Form (2) increased patients' anxiety. CONCLUSION: While the formal quality of all information forms is appreciated by patients both their reading ease score and figures should be improved. A significant reduction of anxiety can be achieved by appropriate selection of the information material.